EP0056565B1 - Derivatives of di(-2-chloroethyl) aminophenyl alanine with antitumour activity - Google Patents

Derivatives of di(-2-chloroethyl) aminophenyl alanine with antitumour activity Download PDF

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Publication number
EP0056565B1
EP0056565B1 EP81830207A EP81830207A EP0056565B1 EP 0056565 B1 EP0056565 B1 EP 0056565B1 EP 81830207 A EP81830207 A EP 81830207A EP 81830207 A EP81830207 A EP 81830207A EP 0056565 B1 EP0056565 B1 EP 0056565B1
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EP
European Patent Office
Prior art keywords
tripeptide
aminoacids
methionine
blocked
compound according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP81830207A
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German (de)
English (en)
French (fr)
Other versions
EP0056565A1 (en
Inventor
Augusto De Barbieri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Proter SpA
Original Assignee
Proter SpA
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Publication date
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Priority to AT81830207T priority Critical patent/ATE10621T1/de
Publication of EP0056565A1 publication Critical patent/EP0056565A1/en
Application granted granted Critical
Publication of EP0056565B1 publication Critical patent/EP0056565B1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the present invention relates to derivatives of dichlorodiethylaminophenylalanine which are useful in the treatments of malignant tumours.
  • Antitumour compounds based on oligopeptides containing m-[di-(2-chloroethyl)amino]-L-phenylalanine are described in AU-B-452,986.
  • the m-[di-(2-chloroethylamino)]-L-phenylalanine is linked through peptide bonds to one or more L-amino-acids to provide respectively di-, or tripeptides.
  • the present invention provide a new family of antitumour compounds each of which is characterized in that it comprises a tripeptide formed from the aminoacids dichlorodiethylaminophenylalanine, para-fluorophenylalanine and methionine bonded together by CO-NH peptide links.
  • each anti-tumour compound has a laevo-rotatory (L) configuration in all the sequences specified above.
  • the N(CH 2 CH 2 CI) 2 ⁇ group may, as stated above, be either in the ortho, meta or para position but this group is preferably in the meta position.
  • aminoacids may be formylated.
  • the preferred process for the preparation of the tripeptides of the invention comprises essentially the steps of:
  • the amine group is acylated, for example, with formic acid or with carbobenzoxy chloride or with other acylating groups which are known in the art.
  • the carboxyl groups are protected, for example, by esterification in the form of methyl, ethyl, propyl or benzyl esters which are subsequently eliminated by cautious saponification or hydrogenolysis.
  • the invention will be more fully described in the following detailed examples of the preparation of one of the tripeptides of the sequence specified above.
  • N formyl-p-fluoro-L-phenylalanyl-m-di(2-chloroethyl)amino-L-phenylalanine ethyl ester.
  • the solution contained 1403 moles of methionine ethyl ester, titrated potentiometrically with 0.1 N HCI0 4 .
  • Dicyclohexylurea was removed by filtration and washed on the filter with 2x20 ml of DMF. 1800 ml of iced water were added gradually to the united filtrates under agitation so as to maintain the temperature below 20°C.
  • the product which separated was collected on a filter, washed with water and dried at 40° to 50°C first in a current of air and then under vacuum over P 2 O 5 .
  • the product obtained was purified by suspension in hot ethyl alcohol and the addition on boiling of a small quantity of DMF until a clear solution was formed.
  • the product d 1 ) with melting point of 188°-190°C was obtained by crystallisation from tetrahydrofuran.
  • the organic phase separated and the aqueous phase was extracted with ethyl acetate (10 ml); the organic extracts were united and washed with 150 mlof cold water and dried with sodium sulphate.
  • the quantity of tripeptide (e,) present in solution was calculated by potentiometric titration with 0.1 N HCIO 4 in acetic acid.
  • the dicyclohexylurea was removed by filtration and washed on the filter with 2x30 ml of DMF. 2 litres of an ice-water mixture were added to the filtrate under agitation at a rate such as to maintain the temperature below 20°C.
  • the product was collected by filtration, and washed on the filter with cold water. It was dried under vacuum at 40°C over P 2 0 5 .
  • the chloroform phase was separated, washed with water, dried, filtered and evaporated under reduced pressure at 40°C.
  • the solution was titrated potentiometrically with 0.1 N HCI0 4 in acetic acid. There were 0.083 moles of c 2 ) in the solution.
  • the dicyclohexylurea was removed by filtration and the filtrate was poured into 1800 ml of cold water (+5°C).
  • the suspension was brought to a pH of 3.5 with 2 N HCI and, after 15 minutes of agitation under cold conditions, the voluminous white product was collected by filtration and washed on the filter with cold water.
  • the product was dried under vacuum at 40°C over P 2 0 5 .
  • Aqueous solutions stabilised with carboxymethylcellulose were administered intraperitoneally or subcutaneously on the first, third, fifth and seventh days after the tumour inoculum; on the ninth day the animals were killed and the weight of the tumours; their percentage variation compared to controls, the weight of the spleen and the body weight were measured.
  • the compounds were tested by injection intraperitoneally or subcutaneously 24 or 48 hours after the tumour inoculum either in a single massive dose or with fractions of the dose at intervals of 8 days, progressively reduced,
  • the tripeptide pFPhe. mMPhe. MetOEtHCI was also tested in AKR mice diagnosed for lymphatic leukaemia induced by the Gross leukaemia virus. At the very beginning of the test the condition of the leukaemic mice was as follows.
  • a single dose of 18-20 mg/kg was injected intraperitoneally or subcutaneously into each mouse.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
EP81830207A 1980-11-28 1981-10-26 Derivatives of di(-2-chloroethyl) aminophenyl alanine with antitumour activity Expired EP0056565B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT81830207T ATE10621T1 (de) 1980-11-28 1981-10-26 Di-(2-chloraethyl)aminophenylalaninderivate mit antitumorwirkung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2630580 1980-11-28
IT26305/80A IT1134503B (it) 1980-11-28 1980-11-28 Composti della diclorodietilaminofenilalanina ad azione antitumorale

Publications (2)

Publication Number Publication Date
EP0056565A1 EP0056565A1 (en) 1982-07-28
EP0056565B1 true EP0056565B1 (en) 1984-12-05

Family

ID=11219187

Family Applications (1)

Application Number Title Priority Date Filing Date
EP81830207A Expired EP0056565B1 (en) 1980-11-28 1981-10-26 Derivatives of di(-2-chloroethyl) aminophenyl alanine with antitumour activity

Country Status (11)

Country Link
US (1) US4428875A (xx)
EP (1) EP0056565B1 (xx)
JP (1) JPS57120559A (xx)
AT (1) ATE10621T1 (xx)
AU (1) AU547065B2 (xx)
CA (1) CA1180697A (xx)
DE (1) DE3167653D1 (xx)
ES (1) ES506871A0 (xx)
IL (1) IL64332A0 (xx)
IT (1) IT1134503B (xx)
PT (1) PT73950B (xx)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4714683A (en) * 1985-01-25 1987-12-22 Oncogen Polypeptide tumor inhibitors and antibodies thereto
US5011777A (en) * 1985-01-25 1991-04-30 Oncogen Vectors encoding brain derivable polypeptide factors
WO1993013089A1 (en) * 1985-01-25 1993-07-08 Urban Frank J Macrocyclic polyether carboxylic acids
US4921941A (en) * 1987-07-01 1990-05-01 Schering Corporation Orally active antiandrogens
US4902781A (en) * 1987-11-24 1990-02-20 Taisho Pharmaceutical Co., Ltd. Novel tripetide derivatives
GR1000608B (el) * 1988-07-21 1992-08-31 Erba Carlo Spa Μεθοδος για την παρασκευη ανταγωνιστων bombesin.
JPH03118130U (xx) * 1990-03-16 1991-12-05
JPH0727940U (ja) * 1993-10-29 1995-05-23 盟和産業株式会社 車輌用フロアマット
DE60141398D1 (de) * 2000-06-13 2010-04-08 Oncopeptides Ab Melphalan-derivate und ihre verwendung als chemotherapeutika gegen krebs
CN100491339C (zh) * 2007-04-20 2009-05-27 苏州市立德化学有限公司 一种抗肿瘤药物美法仑的合成工艺

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU452986B2 (en) * 1971-11-03 1974-09-19 Istituto Sieroterapico Milanese Serafino Belfanti OLIGOPEPTIDES CONTAINING m-jpi (2 CHLORETHYL) AMINO] L-PHENYLALANINE
DE2510634A1 (de) 1975-03-12 1976-09-23 Boehringer Mannheim Gmbh L-3-(3,4-dihydroxy-phenyl)-2- methyl-alanin-peptide und verfahren zu deren herstellung
FR2381023A1 (fr) 1977-02-18 1978-09-15 Delalande Sa Nouveaux oligopeptides trifluoromethyles derives de la l-alanine, leur procede de preparation et leur application en therapeutique
US4216208A (en) * 1978-07-31 1980-08-05 Proter S.P.A. N-Acyl derivatives of glucosamines having antitumor chemotherapeutic activity

Also Published As

Publication number Publication date
DE3167653D1 (en) 1985-01-17
ES8206449A1 (es) 1982-08-16
JPS57120559A (en) 1982-07-27
EP0056565A1 (en) 1982-07-28
ATE10621T1 (de) 1984-12-15
IT8026305A0 (it) 1980-11-28
IT1134503B (it) 1986-08-13
CA1180697A (en) 1985-01-08
ES506871A0 (es) 1982-08-16
IL64332A0 (en) 1982-02-28
JPH0243727B2 (xx) 1990-10-01
AU7739781A (en) 1982-06-03
AU547065B2 (en) 1985-10-03
US4428875A (en) 1984-01-31
PT73950B (fr) 1983-04-18
PT73950A (fr) 1981-12-01

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